Elsevier

Brain Research

Volume 1368, 12 January 2011, Pages 248-253
Brain Research

Research Report
Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice

https://doi.org/10.1016/j.brainres.2010.10.014Get rights and content

Abstract

We previously demonstrated that high doses of methamphetamine (MA) exacerbate damage induced by severe brain trauma. The purpose of the present study was to examine if MA, at low dosage, affected abnormalities in locomotor activity and dopamine turnover in a mouse model of mild traumatic brain injury (mTBI). Adult male CD1 mice were treated with MA (5 mg/kg i.p.) or vehicle 30-min prior to mTBI, conducted by dropping a 30 g metal weight onto the temporal skull, anterior the right ear. At 15 min after mTBI, animals were put into locomotor activity chambers for up to 72 h. During the first 3 h, mTBI alone, compared with vehicle control, did not alter total distance travelled. Treatment with MA significantly increased locomotor activity in the control animals during the first 3 h; mTBI reduced MA-induced hyperactivity. In contrast, at 2 and 3 days after injury, mTBI or MA alone reduced locomotor activity. Co-treatment with MA and mTBI further reduced this activity, suggesting a differential and temporal behavioral interaction between MA and mTBI during acute and subacute phases after injury. Dopamine and DOPAC levels in striatal tissue were analyzed using HPLC-ECD. At 1 h after mTBI or injection, DA was not altered but DOPAC level and DOPAC/DA turnover ratios were significantly reduced. Co-treatment with MA further reduced the DOPAC/DA ratio. At 36 h after injury, mTBI increased tissue DA levels, but reduced DOPAC levels and DOPAC/DA ratios. Co-treatment with MA further reduced DOPAC/DA ratios in striatum. In conclusion, our data suggest that low dosage of MA worsens the suppression of locomotor responses and striatal dopamine turnover after mTBI.

Research Highlights

► Low dose of methamphetamine potentiates mTBI-mediated suppression of dopamine turnover and behavioral immobilization. ► There is a differential and temporal behavioral interaction between methamphetamine and mTBI during acute and subacute phases after injury. ► Exposure to low dose of methamphetamine increases functional deficits after mTBI.

Introduction

Traumatic brain injury (TBI) has become an increasingly common cause of brain damage. According to a recent report from the Centers For Disease Control and Prevention, at least 1.4 million people sustain a TBI each year in U.S.A. Recently, there is high incidence of TBI amongst soldiers injured in the military operations (Hoge et al., 2008). Several studies have indicated that use of drugs is common in neurotrauma patients. In a systemic review of traumatic brain injury and substance misuse, about 36–51% of patients showed use of some substance on emergency admission to hospital (Parry-Jones et al., 2006).

Methamphetamine (MA), a prevalent drug of abuse, has been found to be associated with brain injury. The use and prevalence of MA have been reported in US military personnel (Klette et al., 2006, Lacy et al., 2008). One study has indicated that 27% of trauma patients used MA; furthermore, these cases were associated with longer hospital stays and hospital charges (Tominaga et al., 2004). Patients with a chronic or acute MA abuse history can develop cerebral hemorrhages in striatum and infarction in the middle cerebral arterial distribution area (Rothrock et al., 1988, Yen et al., 1994). Some patients using the anorexiant phentermine, an analog of amphetamine, developed ischemic stroke (Kokkinos and Levine, 1993). In animal studies, MA was found to activate programmed cell death and facilitate ischemic brain damage (Shen et al., 2008, Wang et al., 2001). Pretreatment with MA potentiates ischemia-mediated P53 expression and cerebral infarction in brain (Wang et al., 2001). High doses of MA induce functional and structural changes in the brain similar to those in TBI (Gold et al., 2009). Taken together, these data suggest that high doses of MA (i.e. the 20–40 mg/kg) potentiate neurodegeneration after severe brain injury (i.e. occlusion of middle cerebral artery). The interaction of low dose of MA and minor insults to the brain has not been reported.

It has been demonstrated that mild traumatic brain injury (mTBI), induced by delivering a 30 g sheer force to the temporal region, did not cause physical signs of damage to skull, scalp and brain in experimental mice (Pan et al., 2003, Zohar et al., 2003). These animals developed a deficiency in cognitive learning ability post-injury (Baratz et al., 2010, Zohar et al., 2003)). Similarly, MA at a dose of 5 mg/kg alone does not produce prominent neurotoxicity and has been used to examine locomotor function in hemiparkinsonian rats in numerous studies. The purpose of the present study was to examine the changes in locomotor function as well as the production of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) after mTBI and low dose MA treatment in mice. The dose of MA and traumatic injury model used in these studies were closer to human pathophysiological conditions and were thus used to model the interactions of MA and brain injury. Our data suggest that low dose MA exacerbates the suppression of locomotor responses and striatal dopamine turnover after mTBI.

Section snippets

Behavior

Adult male CD1 mice were used for behavior study. Animals were equally divided into 4 groups. (A) MA: These animals received MA injection (5 mg/kg, i.p.). (B) mTBI: Mice received saline injection (1 ml/1 kg, i.p.) and mTBI at 30 min later. See Experimental procedures). (C) mTBI+MA: Mice received MA injection (5 mg/kg, i.p.) and followed by mTBI 30 min later. (D) vehicle control: These animals received only saline injection. All animals were kept in the activity chambers for 3 h to 3 days with food and

Discussion

In this study, we examined the behavioral and biochemical changes elicited by the interaction of MA and mTBI in mice. We found that MA and mTBI have dual effects on locomotor activity in the acute and subacute phases after drug administration. In the acute phase, MA alone increased total distance travelled in the first 3 h after injection. mTBI did not alter this locomotor activity but suppressed MA-induced hyperactivity. In the subacute phase, MA or mTBI alone reduced locomotor activity.

Animals and mTBI

Adult CD1 mice, purchased from Charles River Laboratories Inc., were housed in a 12-h dark (6pm to 6 am) and 12 h light (6 am to 6 pm) cycle. Animals were treated with saline (1 ml/kg) or (+) methamphetamine (5 mg/kg), and were anesthetized with isoflorane at 30 min following drug administration for mTBI. mTBI was conducted by dropping a 30 g metal projectile onto the temporal skull, anterior the right ear as previously described (Pan et al., 2003, Zohar et al., 2003). Anesthetized mice were laid on

Acknowledgments

This study was supported by the National Institute on Drug Abuse, IRP, U.S.A. and National Science Council of Taiwan (NSC98-2314-B-038-011-MY3).

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